Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2).

We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate-severe in boys but mild-moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients.

Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The recognition of the 17q21.31 microdeletion syndrome has been facilitated by high resolution microarray technology. Recent clinical delineation of this condition emphasises a typical facial appearance, cardiac and renal defects, and speech delay in addition to intellectual disability, hypotonia and seizures. METHODS AND RESULTS: We describe 11 previously unreported patients expanding the phenotypic spectrum to include aortic root dilatation, recurrent joint subluxation, conductive hearing loss due to chronic otitis media, dental anomalies, and persistence of fetal fingertip pads. Molecular analysis of the deletions demonstrates a critical region spanning 440 kb involving either partially or wholly five genes, CRHR1, IMP5, MAPT, STH, and KIAA1267. CONCLUSION: These data have significant implications for the clinical diagnosis and management of other individuals with 17q21.31 deletions.

Oto-palato-digital syndrome, type II: report of three cases with further delineation of the chondro-osseous morphology.

Oto-palato-digital syndrome type II (OPD II) is a lethal X-linked skeletal dysplasia with pleiotropic manifestations. The basic defect is not known. There has been only one detailed report of the chondro-osseous abnormalities in this condition describing abnormal periosteal ossification in a single case [1990: Am J Med Genet 36:226-231]. We report on three cases of OPD II emphasizing the chondro-osseous morphology. Although endochondral ossification was normal, periosteal ossification was defective with islands of cortical bone aplasia and hyperplasia of the periosteum. The trabecular bone was also extremely poorly formed and markedly hypercellular. Both membranous ossification and bone remodeling appear to be defective in OPD II and should account for part of the observed phenotype. The biglycan gene maps to Xq28 and is involved in bone formation, but was excluded as a candidate by direct sequencing of cDNA in one case.

Two further cases of Ohdo syndrome delineate the phenotypic variability of the condition.

Ohdo syndrome (MIM 249620) is a multiple malformation syndrome characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability. A wide range of dysmorphic features and congenital abnormalities have been described in cases reported as Ohdo and Ohdo-like syndromes. We report a further two cases of Ohdo syndrome, one with mild features and the other more severely affected, illustrating the phenotypic variability of the condition. A review of the literature highlights the severe phenotype associated with distinctive facial features, as seen in Case 2 in this report All cases with the severe phenotype have been sporadic. Subtelomeric FISH studies of all chromosome arms on the two cases showed no abnormality. We propose clinical criteria for the diagnosis of Ohdo syndrome and delineate features of the severe phenotype.

Amelogenesis imperfecta: a classification and catalogue for the 21st century.

Amelogenesis imperfecta (AI) is a collective term for a number of conditions with abnormal enamel formation. Many cases are inherited, either as an X-linked, autosomal dominant or autosomal recessive trait. Several classifications have evolved since 1945, based primarily on phenotype with the mode of inheritance being used in some systems as a secondary factor in allocating a case into a particular category. The benefits and shortcomings of these systems are reviewed. As we move into an era of establishing the molecular basis of AI we propose a robust mechanism for classification and cataloguing of the disorder which parallels systems used in medical genetics. This system is applicable to individuals and families irrespective of current or future knowledge of the molecular defect involved. We argue that this system is of more benefit to these individuals and families than previous classifications.

It's only teeth - are there limits to genetic testing?

Dental genetic disorders can cause severe social and psychological effects in affected individuals. The cost of treatment can be considerable, not only in financial terms but also in time spent during treatment. In theory it is, or will soon be, possible to use advances in molecular genetics for pre-natal testing, for selection of embryos using in vitro fertilization techniques, and for gene therapy. The questions we pose are whether these approaches are appropriate. We hope that this review will stimulate debate on these issues.

Clinical and radiographic features of a family with autosomal dominant amelogenesis imperfecta with taurodontism.

This paper describes the clinical features of a family of four generations with autosomal dominant amelogenesis imperfecta with taurodontism (ADAIT). Considerable variation in phenotype was seen, both between individuals and within the dentition of some individuals. Many of the adults had received extensive dental restorative work. These findings re-enforce previous observations of variable phenotype in this and other forms of the condition and add to the argument for a revision of methods of classification. This history of this large family draws further attention to the restorative demands of this group of dental anomalies and, by their generous co-operation, will prove an invaluable help in the investigation by molecular genetic techniques of this disfiguring condition.

Molecular analysis for genetic counselling in amelogenesis imperfecta.

OBJECTIVE: To use molecular genetics to establish the mode of inheritance in a family with amelogenesis imperfecta. MATERIALS AND METHODS: The polymerase chain reaction was used to amplify exons of the amelogenin gene on the short arm of the X chromosome. RESULTS: A single base deletion mutation in exon 6 of the amelogenin gene was identified. This mutation was a single base deletion of a cytosine residue - 431delC - in codon 96 of exon 6, introducing a stop codon 30 codons downstream of the mutation in codon 126 of the exon. CONCLUSION: The firm establishment of an X-linked mode of inheritance affects the genetic counselling for this family.